NOD mice spontaneously develop Type 1 Diabetes (T1D) due to a loss of T cell tolerance to islet antigens. Congenic strains of NOD mice that are highly protected from the occurrence of T1D, because they have multiple resistance alleles situated on two chromosomes (ldd3/5 mice) or 3 linked resistance alleles on a single chromosome (Idd9), do not harbor high-avidity, islet-specific CDS T cells. In order to delineate the mechanism by which CDS tolerance is restored, we will trace the path of naive, islet-specific CDS cells in situations where resistance alleles at multiple or single Idd loci are expressed only in particular cell types. This will provide an assay that will identify the cell(s) that must express specific protective Idd genes to achieve CDS tolerance. We will then correlate gene expression of candidate Idd genes within the relevant cell populations obtained from NOD or congenic mice with the functional consequences that relate to protection from autoimmunity. Although four of the subregions, Idd3, Idd5.1, Idd5.2 and Idd9.3 are relatively well-characterized and the likely molecular basis of disease susceptibility is known in each case, Idd5.3, Idd9.2, and Idd9.1 require further efforts to positionally clone the Idd genes. Relevance: The occurrence of T1D in humans and mice has been mapped to a number of genetic susceptibility loci that prevent T cell tolerance to islet antigens. By elucidating naturally occurring mechanisms that restore such tolerance (as defined by Idd genes that prevent disease), we will better understand the etiology of the disease and also identify targets for interventions that can be used to prevent T1D.